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Tetra-O-substituted butane-bridge modified NDGA derivatives, their synthesis and pharmaceutical use

a technology of tetra-o-substituted butane bridge and derivatives, applied in the field of nordihydroguaiaretic acid derivatives, can solve the problems of poor water solubility, limited application for certain drug action studies, and unstable stability, and achieves a relatively short half-life in aqueous solution

Active Publication Date: 2012-07-31
ERIMOS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to novel compounds, methods of making them, and their use in treating diseases. Specifically, the invention is about a new compound called BB-N, which is a butane bridge-modified version of the compound NDGA. The invention also includes a new compound called BB-Sb4N, which is a tetra-O-substituted version of NDGA. These compounds have been found to have potent inhibitory effects on the growth of cancer cells and can be used to treat diseases such as viral infections, inflammation, metabolic diseases, vascular diseases, and proliferative diseases. The invention also includes pharmaceutical compositions containing these compounds and methods of making them."

Problems solved by technology

While M4N (Formula II) is a strikingly effective and non-toxic anticancer agent, M4N and several other methylated NDGAs, all show poor water solubility which somewhat limit their application for certain drug action studies.
G4N is a very effective mutation-insensitive inhibitor to HIV-1, HSV-1 and HSV-2.17, 22 However, it is somewhat unstable and has a relatively short half-life in aqueous solution, reportedly due to the ester bonds connecting the dimethyl glycine moieties on the NDGA main skeleton.18

Method used

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  • Tetra-O-substituted butane-bridge modified NDGA derivatives, their synthesis and pharmaceutical use
  • Tetra-O-substituted butane-bridge modified NDGA derivatives, their synthesis and pharmaceutical use
  • Tetra-O-substituted butane-bridge modified NDGA derivatives, their synthesis and pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 1,4-bis-(3,4-methoxyphenyl)butane (C20H26O4, FW=330.42) “Compound A”

[0141]

[0142]The compound was synthesized using a modification of Nakamura, et al.20 involving coupling of 1,4-diiodobutane with Grignard reagent derived from 3,4dimethoxybromobenzene in 43% yield. m.p. 93-94° C. (literature21 m.p. 91-92° C.). HPLC purity: 99.25%.

[0143]1HNMR (CDCl3, 300 MHz): δ=1.58-1.68 (m, 4H), 2.55-2.65 (m, 4H), 3.85 (s, 6H), 3.86 (s, 6H), 6.69 (s, 2H), 6.70 (dd, J=7.9, 1.6 Hz, 2H), 6.78 (d, J=7.9 Hz, 2H) ppm, consistent with the structure.

[0144]13CNMR (CDCl3, 75 MHz): δ=31.1, 35.3, 55.7, 55.9, 111.2, 111.7, 120.1, 135.2, 147.0, 148.7 ppm; consistent with the structure.

[0145]Analysis: calculated for C20H26O4, C: 72.70, H: 7.95; found C: 72.51, H: 7.82.

[0146]MS (EI), m / e=331 (M+1); consistent with C20H26O4

example 2

Synthesis of 1,4-bis-(3,4-hydroxyphenyl)butane (alternatively named 1,4-bis(catechol-4-yl)-butane) [C16H18O4, FW=274.31) “Compound B”

[0147]

[0148]This compound was synthesized by cleavage of the aromatic methoxy group of the product of Example 1, (1,4-bis-(3,4-methoxyphenyl) butane), using boron tribromide22 in quantitative yield. The crude product was found to be pure by TLC, so it was used for the preparation of derivatives without further purification. Analytical sample was purified by a flash silica gel chromatographic column using dichloromethane and methanol (95:5, V / V) as eluant.

[0149]m.p 140-142° C. HPLC purity: 98.5%.

[0150]1H NMR (DMSO-d6, 300 MHz): δ=1.60 (t, J=6.5 Hz, 4H, 2 CH2), 2.65 (t, J=6.5 Hz, 4H, 2 CH2), 6.65-6.85 (m, 6H, 6 Ar—H), 9.56 (brs, 4H, 40H) ppm; consistent with the structure.

[0151]13C NMR (DMSO-d6, 75 MHz): δ=31.5, 36.3, 114.5, 115.8, 120.1, 136.5, 143.5, 145.5 ppm, consistent with the structure.

[0152]MS (EI), m / e=275 (M+1), consistent with C16H18O4.

[0153]A...

example 3

Synthesis of 1,4-bis-(3,4-ethoxyphenyl)butane (C24H34O4, FW=386.52) “Compound C”

[0154]

[0155]To a solution of 1,4-bis-(3,4-hydroxyphenyl)butane from Example 2 (700 mg, 2.56 mmol) in acetone (26 mL) was added potassium carbonate (2.39 g, 16.9 mmol, 6.6 equivalents) and iodoethane (2.40 g, 15.4 mmol, 6.0 equivalents) and the mixture heated to reflux for 24 hours. TLC of the reaction indicated completion of the reaction. The reaction mixture was cooled to room temperature, filtered and the solids were washed with acetone. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL). The aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (1.06 g), which was crystallized from ethyl acetate -isopropanol (1:1, 6 mL) to give a pure crystalline product (700 mg, 70% yield).

[01...

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Abstract

The present invention relates to nordihydroguaiaretic acid derivative compounds, namely, butane bridge modified nordihydroguaiaretic acid (NDGA) compounds and butane bridge modified tetra-O-substituted NDGA compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them and kits including them for the treatment of diseases and disorders, in particular, diseases resulting from or associated with a virus infection, such as HIV infection, HPV infection, or HSV infection, an inflammatory disease, such as various types of arthritis and inflammatory bowel diseases, metabolic diseases, such as diabetes and hypertension, or a proliferative disease, such as diverse types of cancers.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is an U.S. National Phase application under 35 U.S.C. §371 of International Patent Application No. PCT / US2007 / 080231, filed Oct. 2, 2007, which claims the benefit of U.S. Provisional Application No. 60 / 827,783, filed Oct. 2, 2006, both of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]The present invention relates to nordihydroguaiaretic acid derivatives, methods of making them and methods of using them for treating viral infections, inflammatory diseases, metabolic diseases, vascular (including cardiovascular) diseases and proliferative diseases, such as cancer.[0003]Nordihydroguaiaretic acid (NDGA, Formula I) has the following chemical structure, in which there are two catechol groups, and a 2,3-dimethylbutane bridge. The butane bridge links two catechol moieties through a 4 position. NDGA is a natural compound that can be isolated from the resin of the leaves of Larrea tri...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/495A61K31/341A61K31/426A61K31/165A61K31/132C07C271/02C07C271/46C07D241/04C07D211/06C07D307/52C07D277/24A61K31/445A61K31/085
CPCC07C37/50C07C255/33C07C43/225C07C43/23C07C47/27C07C47/273C07C217/20C07D277/24C07D295/088C07C39/367C07C217/54C07C39/21C07C43/2055C07C39/16A61P3/00A61P3/12A61P9/00A61P29/00A61P31/00A61P31/12A61P35/00A61P43/00
Inventor CHEN, QINGQIHELLER, JONATHAN DANIELLOPEZ, ROCIO ALEJANDRAMORRIS, AMANDA JEAN
Owner ERIMOS PHARMA
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